The present disclosure relates to KRT19 (cytokeratin 19)-HER2/erbB2/neu (human epidermal growth factor receptor 2) interaction and the use thereof, and more particularly, to the development of a method of treating HER2-positive cancer, and an anticancer drug, using the interaction between KRT19 and HER2 and related molecular mechanisms.
HER2 is a member of the epidermal growth factor receptor (EGFR) family, one of important signaling systems that involve in the proliferation and survival of breast cancer cells. The receptor tyrosine kinases of the EGFR family consist of four receptors: erbB1, HER2/erbB2, erbB3 and erbB4, and they are known to involve in the regulation of adhesion, migration and differentiation of cells as well as cell proliferation and survival. Among all four erb family members, HER2/erbB2 does not bind any ligand; however, it is known to be the most potent oncogene in breast cancer.
Whereas in a case that HER2 levels are normal, HER2 involves in the growth and development of normal breast tissue, abnormal overexpression or amplification of HER2 causes the disruption of normal cellular regulation and the formation of aggressive tumor cells in breast tissue. For this process, HER2 is activated by the oligomerization with other members of EGFR family, and the activated HER2 phosphorylates a number of downstream molecules that in turn activate a variety of signaling cascades. Among these, SOS-Ras-Raf-MEK-MAPK signaling pathway involved in cell proliferation and PI3K-Akt signaling pathway inhibiting apoptosis are representative mechanisms for cancer proliferation.
Preclinical and clinical studies showed that HER2 overexpression is an important phenomenon which occurs from early-stage of cancer incidence and plays an important role in the growth and progression of cancer. Overexpression of HER2 occurs in approximately 20-30% of invasive breast cancers and overexpression is known to involve in poor prognosis of breast cancer that is more malignant and aggressive.
There is much interest in HER2 in the breast cancer research because amplification or overexpression of HER2 has value as a prognostic marker and as a predictive factor for response to treatment in breast cancer patients. There is a controversy about the value as a prognostic factor; however, reports that a bad prognosis and significantly short survival time have been observed with amplification of HER2 gene and the consequent overexpression of protein have been presented through many conferences.
Especially, in metastatic or primary breast cancer patients, the amplification or overexpression of HER2 becomes a decisive marker for the treatment of cancer patients using Herceptin, a monoclonal antibody drug. The importance of HER2 was appreciated and in the year 2000, and HER2 was included in tumor markers for breast cancer proposed by ASCO (American Society of Clinical Oncology), and most guidelines for treatment recommended that HER2 test be carried out for all primary breast cancer patients. Accordingly, there is a need for standardized assessment of HER2 in breast cancer tissue.
However, conventional methods of diagnosis and treatment using Herceptin showed low sensitivity and thus exhibited very low efficiency for a low level of HER2. Thus, there was a need for investigation of molecular mechanism involved in the overexpression of HER2, to find a method of detecting only HER2-overexpressing cells effectively and inhibiting their HER2 expression.
Accordingly, as a result of studies to identify the relations of KRT19 expression in the HER2-overexpressing cells and molecular mechanisms thereof, the present inventors found newly that KRT19 is involved in the MEK/ERK pathway and the Atk kinase-mediated phosphorylation on Ser35 and binds to HER2 to contribute to the stability of HER2. Therefore, the present invention has been completed by finding out anticancer effects which can inhibit the stability of HER2 through the inhibition of KRT19 expression.